Abstract
Combined CDK4/6 and MEK inhibition blocks Kras-mutant cell growth and induces NK cell surveillance.
Major finding: Combined CDK4/6 and MEK inhibition blocks Kras-mutant cell growth and induces NK cell surveillance.
Mechanism: RB-dependent activation of the senescence-associated secretory phenotype induces NK-cell activity.
Impact: Evasion of senescence and immune surveillance in tumors can be reversed by some targeted therapies.
Targeted anticancer therapies block tumor cell–autonomous signaling pathways, but these agents may also have tumor-extrinsic effects on host cells that could contribute to antitumor efficacy. Following previous observations that the combination of CDK4/6 and MEK inhibitors could block the proliferation of KRAS-mutant cancer cells and have immunomodulatory effects on T cells, Ruscetti, Leibold, Bott, and colleagues evaluated the non-tumor cell–autonomous effects of combined treatment with palbociclib (a CDK4/6 inhibitor) and trametinib (a MEK inhibitor) on the immune system in a syngeneic orthotopic model of Kras-mutant;Trp53-null lung cancer. No changes in macrophage infiltration or T-cell activation were observed in the lungs of treated mice, but natural killer (NK) cell accumulation was significantly increased in mice receiving combination therapy compared with single-agent treatment. Depletion of NK cells reduced the efficacy of combination but not single-agent treatment, suggesting that the efficacy of combined CDK4/6 and MEK inhibition in this model was dependent on tumor-extrinsic effects of NK cells. Palbociclib and trametinib are known to cooperate to prevent phosphorylation and inactivation of RB, which plays a key role in both cell-cycle arrest and cellular senescence. Only combination-treated tumor cells showed an increase in senescence markers and upregulation of a program of microenvironment-modulating proteins known as the senescence-associated secretory phenotype (SASP). SASP factors include secreted cytokines like TNFα that promote NK cell proliferation and activation as well as cell-surface NK adhesion modules like ICAM1, both of which were required for the antitumor efficacy of palbociclib plus trametinib in orthotopic as well as autochthonous Kras-mutant;Trp53-null lung cancer models. These findings illustrate that, in addition to their cell-autonomous effects on tumors, some targeted therapy combinations can also exert antitumor activity through restoration of senescence and NK cell–dependent immune surveillance.
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